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WO2022017440A1 - Inhibiteur du récepteur 5-ht2a ou agoniste inverse, procédé de préparation associé, et application associée - Google Patents

Inhibiteur du récepteur 5-ht2a ou agoniste inverse, procédé de préparation associé, et application associée Download PDF

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Publication number
WO2022017440A1
WO2022017440A1 PCT/CN2021/107774 CN2021107774W WO2022017440A1 WO 2022017440 A1 WO2022017440 A1 WO 2022017440A1 CN 2021107774 W CN2021107774 W CN 2021107774W WO 2022017440 A1 WO2022017440 A1 WO 2022017440A1
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Prior art keywords
straight
branched
independently selected
hydrogen atom
chain
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PCT/CN2021/107774
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English (en)
Chinese (zh)
Inventor
张睿
叶亮
马明旭
王文艳
代玉森
田京伟
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Shandong Luye Pharmaceutical Co Ltd
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Shandong Luye Pharmaceutical Co Ltd
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Priority to EP21847375.9A priority Critical patent/EP4186893A4/fr
Priority to JP2023504487A priority patent/JP2023535926A/ja
Priority to CN202180006171.3A priority patent/CN114728933B/zh
Priority to US18/005,952 priority patent/US20230348421A1/en
Priority to CN202310590636.5A priority patent/CN116730981B/zh
Publication of WO2022017440A1 publication Critical patent/WO2022017440A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Definitions

  • the invention relates to a class of compounds as selective serotonin 2A (5-HT 2A ) receptor inhibitors or inverse agonists, a preparation method thereof, and applications in the field of diseases related to 5-HT 2A receptors.
  • Parkinson's disease is a common neurodegenerative disease with an average age of onset around 60 years old (Degirmenci, Yildiz. Cumhuriyet Medical Journal (2017), 39(3), 509-517.). According to the National Institutes of Health (NIH) data in 2018, there are about 4 to 6 million Parkinson's patients worldwide, and as many as 50% of Parkinson's patients will have severe hallucinations or delusions during their illness. Symptoms seriously affect the quality of life of patients and have high morbidity and mortality.
  • NASH National Institutes of Health
  • Pimavanserin acts on the 5-HT 2A receptor, a major excitatory receptor subtype in the 5-HT receptor family, which belongs to ligand-gated channels and G protein-coupled receptors.
  • 5-HT 2A receptor function is closely related to neuronal excitation, behavioral effects, learning and memory, and anxiety, and is an important target for antipsychotic drugs and schizophrenia treatment (Price, DL, et al. Behavioural Pharmacology (2012) , 23(4), 426-433.). Since the main first generation of antipsychotic drugs which inhibit dopamine D 2 receptor, we have severe extrapyramidal side effects. The second generation antipsychotics in addition to inhibiting D 2 receptors, further more specific inhibition of 5-HT receptors particularly 5-HT receptors.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • At least one of X 1 and X 4 is N, and the other is optionally CR 1 or N;
  • X 2 and X 3 are each independently selected from CR 1 and N;
  • X 5 is independently selected from CR 3a , N;
  • X 6 is independently selected from CR 3b , N;
  • X 7 is independently selected from CR 3c , N;
  • X 8 is independently selected from CR 3d , N;
  • Group B is a C 1-6 straight or branched chain alkyl group, a 5-6 membered aza-heterocyclic group, the C 1-6 straight or branched chain alkyl group, or a 5-6 membered aza-heterocyclic group optionally substituted with one or more deuterium atoms;
  • Each R 1 is the same or different, and each is independently selected from a hydrogen atom, a C 1-10 straight-chain or branched-chain alkyl group, and a halogen;
  • Each R 2 is the same or different, and is independently selected from a hydrogen atom, a deuterium atom, a C 1-10 straight or branched chain alkyl group, a (C 1-6 straight chain or branched chain alkyl group) 2 amine group, 3-8 membered cycloalkyl, the C 1-10 linear or branched alkyl, (C 1-6 linear or branched alkyl) 2 amino, or 3-8 membered cycloalkyl are any optionally substituted with one or more deuterium atoms;
  • R 3 , R 3a , R 3b , R 3c , R 3d are the same or different, each independently selected from hydrogen atom, halogen, hydroxyl, C 1-10 linear or branched alkyl, C 1-10 linear or Branched alkoxy, C 1-10 straight or branched haloalkoxy, wherein the C 1-10 straight or branched alkyl, C 1-10 straight or branched alkoxy The group is substituted by one or more substituents selected from hydrogen atom, halogen, hydroxyl, C 1-10 linear or branched alkoxy;
  • each R 4 is independently selected from hydrogen atom, halogen, C 1-10 straight or branched alkyl, C 1-10 straight or branched alkoxy, C 1 -10 linear or branched halogenated alkoxy, wherein the C 1-10 linear or branched alkyl, C 1-10 linear or branched alkoxy are selected from hydrogen atom, hydroxyl, Substituted by one or more substituents in C 1-10 linear or branched alkoxy groups;
  • X is selected from -NH-, -(CH 2 ) 1-4 NH-;
  • Y is selected from O or S
  • n and n are independently selected from 0, 1, 2 and 3;
  • s is independently selected from 1, 2, 3, 4, 5 and 6;
  • y is independently selected from 0, 1, 2, 3, 4 and 5.
  • At least one of X 1 and X 4 is N, and the other is optionally CR 1 ;
  • X 2 and X 3 are each independently selected from CR 1 , preferably CH.
  • X 1 and X 4 are both N, and X 2 and X 3 are each independently selected from CR 1 .
  • At least one of X 1 and X 4 is N, the other is optionally CR 1 , at least one of X 2 , X 3 is N, and the other is optionally CR 1 .
  • X 1 and X 4 are both N, at least one of X 2 , X 3 is N, and the other is optionally CR 1 .
  • At least one of X 1 and X 4 is N, the other is optionally CR 1 , and X 2 and X 3 are both N.
  • X 1 and X 4 are both N, and X 2 and X 3 are both N.
  • X 1 is N and X 2 , X 3 and X 4 are all CR 1 .
  • the group B is -CH 2 -, - (CH 2 ) 2 -, - (CH 2) 3 -, - (CH 2) 4 -, - CD 2 -, -(CD 2 ) 2 -, -(CD 2 ) 3 -, -(CD 2 ) 4 -,
  • R 2 is independently selected from dimethylamine, diethylamine, said dimethylamine, diethylamine radicals are optionally substituted with one or more deuterium atoms;
  • R 2 is independently selected from a hydrogen atom, a deuterium atom, a methyl, ethyl, propyl, isopropyl propyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl, butyl , isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted with one or more deuterium atoms.
  • each R 1 is the same or different and each is independently selected from a hydrogen atom, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl base, isobutyl, sec-butyl, tert-butyl.
  • each R 2 is the same or different and each is independently selected from a hydrogen atom, a deuterium atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl , sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-Butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted with one or more deuterium atoms.
  • R 3 , R 3a , R 3b , R 3c , R 3d are the same or different and are each independently selected from hydrogen, F, Cl, Br, I, hydroxy, methyl , ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1 , 1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl, oxy, ethoxy, propoxy, isopropoxy group, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, fluoromethoxy, difluoromethoxy, trichloromethoxy, trifluo
  • X 6 is CR 3b
  • X 6, R 3 form a ring system together with the atoms to which they are attached, and optionally substituted by one or more identical or different R 4 is substituted.
  • the ring system is preferably selected from dihydrofuran, dihydropyrrole, and dihydrothiophene.
  • each R 4 is the same or different, and each is independently selected from hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.
  • any one of the compounds of formula (I) described above may be a deuterated analog thereof.
  • the deuterated analogs refer to analogs in which one or more hydrogen atoms of a compound are replaced by deuterium atoms.
  • the compounds of formula (I) provided by the present invention have higher 5-HT 2A antagonistic activity, 5-HT 2A inverse agonistic activity, and/or lower cardiotoxicity.
  • X 1 and/or X 4 are N
  • X 2 and X 3 are CH
  • the 5-HT 2A antagonistic activity and/or the 5-HT 2A inverse agonistic activity can be further enhanced.
  • the present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • X 3 , X 4 are each independently selected from CR 1 , N;
  • X 5 is independently selected from CR 3a , N;
  • X 7 is independently selected from CR 3c , N;
  • X 8 is independently selected from CR 3d , N;
  • Each R 1 is the same or different, and each is independently selected from a hydrogen atom, a C 1-10 straight-chain or branched-chain alkyl group, and a halogen;
  • R 2 is independently selected from hydrogen atom, deuterium atom, C 1-10 linear or branched alkyl, (C 1-6 linear or branched alkyl) 2 amine group, 3-8 membered cycloalkyl , the C 1-10 linear or branched alkyl, (C 1-6 linear or branched alkyl) 2 amine group, or 3-8 membered cycloalkyl are optionally replaced by one or more Deuterium atom substitution;
  • R 3 , R 3a , R 3c and R 3d are the same or different, each independently selected from hydrogen atom, halogen, hydroxyl, C 1-10 linear or branched alkyl, C 1-10 linear or branched Alkoxy, C 1-10 straight or branched chain haloalkoxy, wherein the C 1-10 straight or branched alkyl, C 1-10 straight or branched alkoxy are selected Substituted from one or more substituents in hydrogen atom, halogen, hydroxyl, C 1-10 linear or branched alkoxy;
  • X is selected from -NH-, -(CH 2 ) 1-4 NH-;
  • Y is selected from O or S
  • n and n are independently selected from 0, 1, 2 and 3;
  • s is independently selected from 1, 2, 3, 4, 5 and 6.
  • X 3 and X 4 are CR 1.
  • X 3 is N
  • X 4 is CR 1.
  • X 3 is CR 1
  • X 4 is N.
  • each R 1 is the same or different and each is independently selected from a hydrogen atom, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl base, isobutyl, sec-butyl, tert-butyl.
  • each R 2 is the same or different and each is independently selected from a hydrogen atom, a deuterium atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl , sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted with one or more deuterium atoms; preferably hydrogen, deuterium, methyl, ethyl, deuterated methyl or deuterium substituted ethyl; more preferably methyl or deuterated methyl.
  • R 3 , R 3a , R 3c , R 3d are the same or different and are each independently selected from hydrogen, F, Cl, Br, I, hydroxy, methyl, ethyl , propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1- Dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl, oxy, ethoxy, propoxy, isopropoxy, butyl Oxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, fluoromethoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy,
  • R 3 and the carbon atom, form a ring system together with the adjacent carbon atoms, and optionally substituted by one or more identical or different substituents R 4.
  • the ring system is preferably selected from dihydrofuran, dihydropyrrole, and dihydrothiophene.
  • each R 4 is the same or different, and each is independently selected from hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.
  • any one of the compounds of formula (II) described above may be a deuterated analog thereof.
  • the deuterated analogs refer to analogs in which one or more hydrogen atoms of a compound are replaced by deuterium atoms.
  • the compounds of formula (II) provided by the present invention have higher 5-HT 2A antagonistic activity, 5-HT 2A inverse agonistic activity, and/or lower cardiotoxicity.
  • the present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
  • X 3 , X 4 are each independently selected from CR 1 , N;
  • X 5 is independently selected from CR 3a , N;
  • X 7 is independently selected from CR 3c , N;
  • X 8 is independently selected from CR 3d , N;
  • Each R 1 is the same or different, and each is independently selected from a hydrogen atom, a C 1-10 straight-chain or branched-chain alkyl group, and a halogen;
  • R 2 is independently selected from hydrogen atom, deuterium atom, C 1-10 linear or branched alkyl, (C 1-6 linear or branched alkyl) 2 amine group, 3-8 membered cycloalkyl , the C 1-10 linear or branched alkyl, (C 1-6 linear or branched alkyl) 2 amine group, or 3-8 membered cycloalkyl are optionally replaced by one or more Deuterium atom substitution;
  • R 3 , R 3a , R 3c and R 3d are the same or different, each independently selected from hydrogen atom, halogen, hydroxyl, C 1-10 linear or branched alkyl, C 1-10 linear or branched Alkoxy, C 1-10 straight or branched chain haloalkoxy, wherein the C 1-10 straight or branched alkyl, C 1-10 straight or branched alkoxy are selected Substituted from one or more substituents in hydrogen atom, halogen, hydroxyl, C 1-10 linear or branched alkoxy;
  • R 3 and the carbon atom, with the adjacent carbon atoms form a ring system, said ring system is selected from dihydro-furan, dihydro-pyrrole, dihydro-thiophene, and substituted by one or more identical or different R 4 substitution, each R 4 is independently selected from hydrogen atom, halogen, C 1-10 straight or branched alkyl, C 1-10 straight or branched alkoxy, C 1-10 straight chain haloalkoxy or branched, wherein said linear or branched C 1-10 alkyl group, C 1-10 linear or branched alkoxy group is selected from a hydrogen atom, hydroxyl, C 1- 10 substituted by one or more substituents in straight-chain or branched-chain alkoxy groups;
  • s is independently selected from 1, 2, 3, 4, 5 and 6.
  • X 3 and X 4 are CR 1.
  • X 3 is N
  • X 4 is CR 1.
  • X 3 is CR 1
  • X 4 is N.
  • each R 1 is the same or different, each independently selected from the group consisting of a hydrogen atom, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl base, isobutyl, sec-butyl, tert-butyl.
  • each R 2 is the same or different and each is independently selected from a hydrogen atom, a deuterium atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl , sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted with one or more deuterium atoms; preferably hydrogen, deuterium, methyl, ethyl, deuterated methyl or deuterium substituted ethyl; more preferably methyl or deuterated methyl.
  • R 3 , R 3a , R 3c , R 3d are the same or different and are each independently selected from hydrogen, F, Cl, Br, I, hydroxy, methyl, ethyl , propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1- Dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl, oxy, ethoxy, propoxy, isopropoxy, butyl Oxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, fluoromethoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy, 2
  • R 3 and the carbon atom form a ring system together with the adjacent carbon atoms, and optionally substituted by one or more identical or different substituents R 4.
  • the ring system is preferably selected from dihydrofuran, dihydropyrrole, and dihydrothiophene.
  • each R 4 is the same or different, and each is independently selected from hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.
  • any one of the compounds of formula (III) described above may be a deuterated analog thereof.
  • the deuterated analogs refer to analogs in which one or more hydrogen atoms of a compound are replaced by deuterium atoms.
  • X 7 is independently selected from CR 3c , N;
  • X 8 is independently selected from CR 3d , N;
  • R 1 is independently selected from hydrogen atom, C 1-10 straight or branched chain alkyl, halogen;
  • R 2 is independently selected from hydrogen atom, deuterium atom, C 1-10 linear or branched alkyl, (C 1-6 linear or branched alkyl) 2 amine group, 3-8 membered cycloalkyl , the C 1-10 linear or branched alkyl, (C 1-6 linear or branched alkyl) 2 amine group, or 3-8 membered cycloalkyl are optionally replaced by one or more Deuterium atom substitution;
  • R 3 , R 3c and R 3d are the same or different, and are each independently selected from hydrogen atom, halogen, hydroxyl, C 1-10 linear or branched alkyl, C 1-10 linear or branched alkoxy , C 1-10 straight or branched chain haloalkoxy, wherein said C 1-10 straight or branched alkyl, C 1-10 straight or branched alkoxy are selected from hydrogen atoms , substituted by one or more substituents in halogen, hydroxyl, C 1-10 linear or branched alkoxy;
  • R 3 and the carbon atom, with the adjacent carbon atoms form a ring system, said ring system is selected from dihydro-furan, dihydro-pyrrole, dihydro-thiophene, and substituted by one or more identical or different R 4 substitution, each R 4 is independently selected from hydrogen atom, halogen, C 1-10 straight or branched alkyl, C 1-10 straight or branched alkoxy, C 1-10 straight chain haloalkoxy or branched, wherein said linear or branched C 1-10 alkyl group, C 1-10 linear or branched alkoxy group is selected from a hydrogen atom, hydroxyl, C 1- 10 substituted by one or more substituents in straight-chain or branched-chain alkoxy groups;
  • s is independently selected from 1, 2, 3, 4, 5 and 6.
  • each R 1 is the same or different and each is independently selected from a hydrogen atom, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl base, isobutyl, sec-butyl, tert-butyl.
  • each R 2 is the same or different, each independently selected from a hydrogen atom, a deuterium atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl , sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-Butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted with one or more deuterium atoms.
  • R 3 , R 3c , R 3d are the same or different and are each independently selected from hydrogen, F, Cl, Br, I, hydroxy, methyl, ethyl, propyl , isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethyl Butyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl, oxy, ethoxy, propoxy, isopropoxy, butoxy, Isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, fluoromethoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy, 2-fluoroethy
  • R 3 and the carbon atom form a ring system together with the adjacent carbon atoms, and optionally substituted by one or more identical or different substituents R 4.
  • the ring system is preferably selected from dihydrofuran, dihydropyrrole, and dihydrothiophene.
  • each R 4 is the same or different, and each is independently selected from hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.
  • any one of the compounds of formula (IV) described above may be a deuterated analog thereof.
  • the deuterated analogs refer to analogs in which one or more hydrogen atoms of a compound are replaced by deuterium atoms.
  • the present invention provides a compound represented by formula (V) or a pharmaceutically acceptable salt thereof,
  • X 4 is independently selected from CR 6 , N;
  • X 7 is independently selected from CR 3c , N;
  • X 8 is independently selected from CR 3d , N;
  • R 1 , R 5 , and R 6 are the same or different, and are each independently selected from a hydrogen atom, a C 1-10 straight-chain or branched-chain alkyl group, and a halogen;
  • R 2 is independently selected from hydrogen atom, deuterium atom, C 1-10 linear or branched alkyl, (C 1-6 linear or branched alkyl) 2 amine group, 3-8 membered cycloalkyl , the C 1-10 linear or branched alkyl, (C 1-6 linear or branched alkyl) 2 amine group, or 3-8 membered cycloalkyl are optionally replaced by one or more Deuterium atom substitution;
  • R 3 , R 3c and R 3d are the same or different, and are each independently selected from hydrogen atom, halogen, hydroxyl, C 1-10 linear or branched alkyl, C 1-10 linear or branched alkoxy , C 1-10 straight or branched chain haloalkoxy, wherein said C 1-10 straight or branched alkyl, C 1-10 straight or branched alkoxy are selected from hydrogen atoms , substituted by one or more substituents in halogen, hydroxyl, C 1-10 linear or branched alkoxy;
  • X 3 and X 4 are CR 5 and CR 6.
  • X 3 is N
  • X 4 is CR 6.
  • R 1 , R 5 , R 6 are the same or different and are each independently selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, iso propyl, butyl, isobutyl, sec-butyl, tert-butyl; preferably F, Cl, Br or I, more preferably F.
  • R 2 is independently selected from a hydrogen atom, a deuterium atom, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl base, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted with one or more deuterium atoms; preferably hydrogen, deuterium, methyl, ethyl, deuterated methyl or deuterated ethyl; more preferably methyl or deuterated methyl.
  • R 3 , R 3c , R 3d are the same or different and are each independently selected from hydrogen, F, Cl, Br, I, hydroxy, methyl, ethyl, propyl , isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethyl Butyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl, oxy, ethoxy, propoxy, isopropoxy, butoxy, Isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, fluoromethoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy, 2-fluoroethy
  • X 3 and X 7 are both CH;
  • X 4 is CR 6 , R 6 is hydrogen atom or halogen, X 4 is preferably CH or CF;
  • X 8 is CR 3d , R 3d is hydrogen atom or halogen, R 3d is preferably hydrogen atom, F, Cl or Br;
  • R 1 is halogen, preferably F
  • R 2 is independently selected from a hydrogen atom, a deuterium atom, C 1-5 straight-chain or branched-chain alkyl group, a C 1-5 straight-chain or branched alkyl group optionally substituted with one or more deuterium atoms ; preferably a hydrogen atom, a deuterium atom, methyl, ethyl, propyl or isopropyl optionally substituted by one or more deuterium atoms; preferably hydrogen atom, methyl or ethyl; more preferably methyl;
  • R 3 is selected from hydroxyl, C 1-10 straight or branched alkyl, C 1-10 straight or branched alkoxy, C 1-10 straight or branched haloalkoxy, wherein the The C 1-10 linear or branched alkyl, C 1-10 linear or branched alkoxy are selected from hydrogen atom, halogen, hydroxyl, C 1-10 linear or branched alkoxy one or more substituents; R 3 is preferably a substituted or unsubstituted C 2-5 straight-chain or branched alkyl group, a substituted or unsubstituted C 2-5 straight-chain or branched, alkoxy group, a substituted or unsubstituted C 2-5 straight-chain or branched haloalkoxy group; R 3 is more preferably an ethoxy, tert-butyl group, isobutoxy, 2-fluoroethoxy, 2 , 2-difluoroethoxy, 2,2,2-trifluoroethoxy, 3-
  • X 3, X 4, X 7 and X 8 are CH;
  • R 1 is a halogen, preferably F;
  • R 2 is methyl;
  • R 3 is selected from halo-substituted alkoxy is C 1- 10 straight chain or branched chain group, preferably C 2-5 linear or branched haloalkoxy, more preferably 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 3-fluoropropoxy, 3,3-difluoropropoxy, 2,2'-difluoroisopropoxy, 3,3,3-trifluoropropoxy, 4-fluorobutoxy, 4, 4-difluorobutoxy or 4,4,4-trifluorobutoxy.
  • any one of the compounds of formula (V) described above may be a deuterated analog thereof.
  • the deuterated analogs refer to analogs in which one or more hydrogen atoms of a compound are replaced by deuterium atoms.
  • the compounds of formula (V) provided by the present invention have higher 5-HT 2A antagonistic activity, 5-HT 2A inverse agonistic activity, and/or lower cardiotoxicity.
  • R 3 is a C 1-10 linear or branched alkoxy group substituted by halogen, and X 3 and X 4 are CH, the antagonistic activity of 5-HT 2A and/or the anti-reaction of 5-HT 2A can be further improved. to agonistic activity.
  • the present invention provides a compound represented by formula (VI) or a pharmaceutically acceptable salt thereof,
  • X 3 is independently selected from CR 5 and N;
  • X 4 is independently selected from CR 6 , N;
  • R 1 , R 5 , and R 6 are the same or different, and are each independently selected from a hydrogen atom, a C 1-10 straight-chain or branched-chain alkyl group, and a halogen;
  • R 2 is independently selected from hydrogen atom, deuterium atom, C 1-10 linear or branched alkyl, (C 1-6 linear or branched alkyl) 2 amine group, 3-8 membered cycloalkyl , the C 1-10 linear or branched alkyl, (C 1-6 linear or branched alkyl) 2 amine group, or 3-8 membered cycloalkyl are optionally replaced by one or more Deuterium atom substitution;
  • R 4a , R 4b , R 4c and R 4d are the same or different, and are each independently selected from hydrogen atom, halogen, hydroxyl, C 1-10 straight or branched alkyl, C 1-10 straight or branched Alkoxy, C 1-10 straight or branched chain haloalkoxy, wherein the C 1-10 straight or branched alkyl, C 1-10 straight or branched alkoxy are selected Substituted from one or more substituents of hydrogen atom, halogen, hydroxyl, C 1-10 linear or branched alkoxy.
  • X 3 and X 4 are CR 5, CR 6.
  • X 3 is N
  • X 4 is CR 6.
  • X 3 is CR 5
  • X 4 is N.
  • R 1 is independently selected from a hydrogen atom, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec Butyl, tert-butyl; preferably F, Cl, Br or I, more preferably F.
  • R 2 are the same or different and are independently selected from hydrogen atoms, deuterium atoms, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl base, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted with one or more deuterium atoms; preferably hydrogen, deuterium, methyl, ethyl, deuterated methyl or deuterated ethyl ; more preferably methyl or deuterated methyl.
  • R 4a , R 4b , R 4c , R 4d are the same or different and are each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl , isobutyl, sec-butyl, tert-butyl.
  • X 3 is CH
  • X 4 is CR 6 , R 6 is hydrogen atom or halogen, X 4 is preferably CH or CF;
  • R 1 is halogen, preferably F
  • R 2 is independently selected from a hydrogen atom, a deuterium atom, C 1-5 straight-chain or branched-chain alkyl group, a C 1-5 straight-chain or branched alkyl group optionally substituted with one or more deuterium atoms ; preferably a hydrogen atom, a deuterium atom, methyl, ethyl, propyl or isopropyl optionally substituted by one or more deuterium atoms; preferably hydrogen atom, deuterium atom, methyl, ethyl, deuterated methyl or deuterated ethyl; more preferably methyl or deuterated methyl;
  • R 4a and R 4b are independently selected from hydrogen atoms, methyl groups, and trifluoromethyl groups; R 4c and R 4d are hydrogen atoms.
  • any one of the compounds of formula (VI) described above may be a deuterated analog thereof.
  • the deuterated analogs refer to analogs in which one or more hydrogen atoms of a compound are replaced by deuterium atoms.
  • the compound of formula (VI) provided by the present invention has higher 5-HT 2A antagonistic activity and/or 5-HT 2A inverse agonistic activity, and lower cardiotoxicity.
  • the present invention provides the following compounds or pharmaceutically acceptable salts, deuterated analogs thereof:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of any of the above-mentioned compounds or a stereoisomer or a pharmaceutically acceptable salt thereof, or a crystal of any of the above-mentioned compounds form and a pharmaceutically acceptable carrier.
  • the carrier includes conventional adjuvant ingredients in the art, such as fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents, antioxidants, and wetting agents.
  • the pharmaceutical composition can be prepared into various pharmaceutically acceptable dosage forms, such as tablets, capsules, oral liquids, suspensions, granules, powders, microparticles, pills, microtablets, fast-dissolving films, Nasal sprays, transdermal patches, injections or various sustained and controlled release preparations, etc.
  • the pharmaceutical compositions can be administered orally, transmucosally, rectally or parenterally (including intravascular, intravenous, intraperitoneal, subcutaneous, intramuscular and intrasternal).
  • the administered dose can be appropriately adjusted according to the patient's age, sex and disease type.
  • the pharmaceutical compositions may be in the form of, for example, tablets, capsules, liquid capsules, suspensions or liquids.
  • the pharmaceutical compositions are preferably prepared in dosage unit form containing specified quantities of active ingredients.
  • the pharmaceutical composition may be provided as a tablet or capsule containing the active ingredient in an amount ranging from about 0.1 to 1000 mg, preferably about 0.25 to 250 mg, and more preferably about 0.5 to 100 mg.
  • Suitable daily dosages for humans or other mammals can vary widely depending on the condition of the patient and other factors, but can be determined using routine methods.
  • the present invention provides the use of any one of the above-mentioned compounds, pharmaceutically acceptable salts or stereoisomers thereof in a medicament for the treatment of 5-HT 2A receptor-related diseases.
  • the diseases or symptoms include: schizophrenia, psychosis, schizoaffective disorder, mania, psychotic depression, affective disorders, dementia, anxiety disorders, sleep disorders, appetite disorders, bipolar disorder, secondary to hypertension psychosis, migraine, hypertension, thrombosis, vasospasm, ischemia, motor convulsions, depression, major depressive disorder, anxiety, sleep and appetite disturbances, non-motor symptoms due to Parkinson's disease, delusions, hallucinations, Depression, anxiety, cognitive impairment, sleep disturbance, dementia-related psychiatric disorders, negative symptoms of schizophrenia, Parkinson's disease, Huntington's disease, Alzheimer's disease, spondylo-cerebellar atrophy, Tourette's syndrome, Friedreich's ataxia, Machado-Joseph disease, dementia with Lewy
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts, organic acid salts, and also salts of amino acids such as arginine and the like, and salts of organic acids such as glucuronic acid (see Berge et al. , “Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977)).
  • Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods.
  • salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the present invention.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
  • the diastereoisomers were resolved and the pure enantiomers recovered.
  • separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium representative of a carrier capable of delivering an effective amount of the active substance of the present invention, without interfering with the biological activity of the active substance, and without toxic side effects to the host or patient, including but not limited to : Binder, filler, lubricant, disintegrant, wetting agent, dispersant, solubilizer, suspending agent, etc.
  • an "effective amount” or “therapeutically effective amount” with respect to a drug or pharmacologically active agent refers to a nontoxic but sufficient amount of the drug or agent to achieve the desired effect.
  • an "effective amount” of one active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition.
  • the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
  • the present invention is intended to include all isotopes of atoms present in the compounds of the present invention.
  • Isotopes include those atoms with the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • Isotopes of carbon include 13 C and 14 C.
  • Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the otherwise used non-labeled reagent.
  • deuterated analog refers to an analog of a compound in which one or more hydrogen atoms have been replaced by a deuterium atom.
  • deuterium atoms optionally substituted with one or more deuterium atoms.
  • group may be unsubstituted by deuterium atoms, or substituted with one or more deuterium atoms, i.e., includes groups that are not substituted with deuterium atoms In the case of deuterated, partially deuterated and/or fully deuterated.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable of.
  • Ketone substitution does not occur on aromatic groups.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, with independent options for R in each case.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • alkyl denotes a straight-chain or branched saturated hydrocarbon chain may be mono-substituted (e.g., -CH 2 F) or substituted (e.g., -CF 3), which can be mono- (e.g. methyl), divalent (eg methylene), or polyvalent (eg methine).
  • C 1- C 10 represents 1 to 10 carbons, and C 1-10 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 and C 10 ;
  • alkyl groups include methyl (Me), ethyl (Et), propyl (eg, n-propyl and isopropyl), butyl (eg, n-butyl, isobutyl, s-butyl) , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl, 1-ethylpropyl), hexyl (eg, n-hexyl, isohexyl, 1,1-dimethyl butyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl), heptyl, octyl, nonyl
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • haloalkoxy is intended to include monohaloalkyl and polyhalogenated straight or branched chain haloalkoxy groups.
  • haloC 1-10 alkoxy is intended to include, but not be limited to, fluoromethoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2 , 2-difluoroethoxy, 2,2,2-trifluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, 3-fluoropropoxy, 3,3-difluoropropoxy, 2,2'-difluoroisopropoxy, 3,3,3-trifluoropropoxy, 4-fluorobutoxy, 4,4-difluorobutoxy, 4,4,4-trifluorobutanyl oxy, 2-fluoro-2-methylpropyl, 5,5,5-trifluoropentyloxy, 6,6,6-trifluorohexyloxy.
  • Haloalkyl is intended to include monohaloalkyl and polyhalogenated straight or branched chain alkyl groups.
  • halo (C 1 -C 4) alkyl is meant to include, but are not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl and 3-bromopropyl and the like Wait.
  • examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • alkoxy represents the aforementioned alkyl groups having the specified number of carbon atoms attached through an oxygen bridge.
  • Typical alkoxy groups include C 1-10 alkoxy groups such as: C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 alkoxy groups.
  • alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, S- pentyloxy, hexyloxy, 2-ethylbutoxy, heptyloxy, octyloxy, nonyloxy, decyloxy, etc.
  • cycloalkyl includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom is saturated, may be mono- or polysubstituted, and may be monovalent, divalent or polyvalent.
  • examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0] Dicyclodecane, etc.
  • Figure 1 Comparison of drug-time curves after oral administration of pimavanserin and compound 59
  • compound 14a (210 mg, 1.0 mmol) was dissolved in 5 ml of acetonitrile, N-(4-isobutoxybenzyl)-1H-imidazole-carboxamide (273 mg, 1.0 mmol), potassium carbonate (207 mg, 1.5 mmol), the temperature was raised to 60 °C and the reaction was stirred for 12 h.
  • compound 1a (446 mg, 2.0 mmol) was dissolved in 10 ml of acetonitrile, 32a (440 mg, 2.0 mmol), HATU (760 mg, 2.0 mmol), diisopropylethylamine (387 mg, 3.0 mmol) were added and the temperature was raised to The reaction was stirred at 60°C for 12h.
  • 63b (1.49 g, 7.63 mmol) was dissolved in 20 ml of methanol, and (5-fluoropyridin-2methyl)amine (962.4 mg, 7.63 mmol), sodium triacetoxyborohydride (1.972 g, 9.31 mmol) were added. mmol), warmed to room temperature and reacted for 15h, added NaHCO 3 aqueous solution to adjust the pH value to basic, concentrated the organic phase, then extracted with dichloromethane (50mL*3), combined the organic phases, dried with anhydrous sodium sulfate, filtered, reduced Concentration column chromatography gave 63c (217 mg).
  • DMEM+10% FBS purchased from GBICO
  • Logarithmic growth phase NIH 3 T3-5HT 2A R cells at a density of 1000 cells per well were seeded in white wall clear bottom 96-well plates, 37 °C, 5% CO 2 incubator overnight The next day, to be The test compound was added to the cells, and the highest concentration of the test compound was 10 uM, which was diluted with PBS at 3.16-fold concentration gradient to 9 concentrations, and each concentration was set up in double wells. PBS was used as the negative control group, and pimavanserin with the same concentration was used as the positive control group. After adding the drug, continue to incubate at 37°C in a 5% CO 2 incubator for 120 hours.
  • Cell culture medium DMEM/F12+10% FBS (purchased from GBICO)
  • CHO-K1/5-HT 2A cells in logarithmic growth phase were seeded in a 384-well plate at a density of 10,000 cells per well, cultured at 37°C in a 5% CO 2 incubator for 16-24 hours, and centrifuged to remove the cell culture plate medium, adding the dye, into 37 °C, 5% CO 2 incubator incubation continued for 1h. Place the cell culture plate on the FLIPR, add the compound to be tested, and detect the Ca 2+ signal.
  • the highest concentration of the compound to be tested is 10uM, and 10 concentrations of the compound to be tested are diluted with 3-fold concentration gradient with PBS.
  • Inhibition rate (%) 100%-[(signal value of compound to be tested-signal value of detection solution)/(maximum signal value-signal value of detection solution)] ⁇ 100%
  • CHO-hERG cell line Choinese hamster ovary cells stably expressing hERG channels
  • CHO cells stably expressing hERG were cultured in a cell culture dish with a diameter of 35 mm, placed in an incubator at 37°C and 5% CO2, and passaged at a ratio of 1:5 every 48 hours.
  • the cell culture medium was aspirated, rinsed with extracellular fluid, and then 0.25% Trypsin-EDTA (Invitrogen) solution was added, and digested at room temperature for 3-5 minutes. The digestion solution was aspirated, and the cells were resuspended in extracellular fluid and transferred to the experimental dish for electrophysiological recording.
  • Cisapride Take 10 ⁇ L of 150 ⁇ M Cisapride DMSO stock solution, transfer it to 4990 ⁇ L extracellular fluid, and dilute 500 times to obtain the final concentration to be tested, 300 nM.
  • hERG potassium channel currents were recorded by whole-cell patch-clamp technique at room temperature.
  • the glass microelectrode is drawn from the glass electrode blank (BF150-86-10, Sutter) by a drawing machine.
  • the tip resistance after filling the electrode liquid is about 2-5M ⁇ . Insert the glass microelectrode into the amplifier probe to connect to the patch clamp amplifier. Clamp voltages and data recording were controlled and recorded by a computer using pClamp 10 software with a sampling frequency of 10 kHz and a filtering frequency of 2 kHz.
  • the cells were clamped at -80mV and the step voltage evoked hERG potassium current (I hERG ) was given a 2s depolarization voltage from -80mV to +20mV, and then repolarized to -50mV for 1s then back to -80mV. This voltage stimulation was given every 10 s, and the dosing process was started after it was determined that the hERG potassium current was stable (1 min). Compounds were administered for at least 1 minute at each concentration tested and at least 2 cells were tested at each concentration (n > 2).
  • Inhibition% represents the inhibition percentage of the compound on hERG potassium current
  • I and Io represent the amplitude of hERG potassium current after drug addition and before drug addition, respectively.
  • Test Example 3 In vitro stability evaluation of pimavanserin and compound 59 in liver microsomes
  • liver microsome working solution Dilute liver microsomes to 0.56 mg/ml with 100 mM phosphate buffer;
  • NADPH reduced nicotinamide adenine dinucleotide phosphate
  • Stop solution configuration Dilute tolbutamide to 20ng/mL with acetonitrile, as stop solution containing internal standard.
  • Pimavanserin purchased from MCE Company.
  • Eight SD rats weighing about 220 grams were randomly divided into 2 groups, 4 rats in each group, fasted for 12 hours before administration, and administered pimavanserin and compound 59 by intragastric administration at a dose of 46.7 ⁇ mol/kg, respectively.
  • Vehicles were all 20% Solutol.
  • Blood was collected before administration and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours after administration, respectively. The blood was placed in a heparinized EP tube, and the plasma was centrifuged to separate the plasma. Plasma concentrations of compounds were determined by LC-MS/MS, and pharmacokinetic parameters were calculated.

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Abstract

La présente invention concerne un nouveau composé en tant qu'inhibiteur du récepteur 5-HT2A ou agoniste inverse, un procédé de préparation associé, et une composition pharmaceutique le comprenant. La présente invention concerne également une application du composé ou de la composition pharmaceutique dans la préparation d'un médicament pour le traitement de maladies associées au récepteur 5-HT2A, les maladies comprenant : des symptômes non moteurs provoqués par la maladie de Parkinson : la délusion, l'illusion, la dépression, l'anxiété, un trouble cognitif et un trouble du sommeil ; des maladies mentales associées à la démence ; un trouble dépressif majeur ; ou des symptômes négatifs de schizophrénie, etc.
PCT/CN2021/107774 2020-07-22 2021-07-22 Inhibiteur du récepteur 5-ht2a ou agoniste inverse, procédé de préparation associé, et application associée Ceased WO2022017440A1 (fr)

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JP2023504487A JP2023535926A (ja) 2020-07-22 2021-07-22 ５－ｈｔ２ａ受容体阻害剤又は逆作動薬、その調製方法、及びその用途
CN202180006171.3A CN114728933B (zh) 2020-07-22 2021-07-22 5-ht2a受体抑制剂或反向激动剂及其制备方法和应用
US18/005,952 US20230348421A1 (en) 2020-07-22 2021-07-22 5-ht2a receptor inhibitor or inverse agonist, preparation method therefor, and application thereof
CN202310590636.5A CN116730981B (zh) 2020-07-22 2021-07-22 5-ht2a受体抑制剂或反向激动剂及其制备方法和应用

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CN115850204B (zh) * 2022-11-26 2024-01-19 烟台大学 四氢苯并噻吩衍生物及其制备方法和应用
WO2025162237A1 (fr) * 2024-02-02 2025-08-07 绿叶嘉奥制药石家庄有限公司 Forme saline et forme cristalline d'un agoniste inverse du récepteur 5-ht2a, son procédé de préparation et son utilisation

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WO2024027800A1 (fr) * 2022-08-03 2024-02-08 嘉奥制药（石家庄）有限公司 Agoniste inverse du récepteur 5-ht2a, son procédé de préparation et son utilisation
CN119630650A (zh) * 2022-08-03 2025-03-14 绿叶嘉奥制药石家庄有限公司 5-ht2a受体反向激动剂及其制备方法和应用
CN119630650B (zh) * 2022-08-03 2025-12-19 绿叶嘉奥制药石家庄有限公司 5-ht2a受体反向激动剂及其制备方法和应用

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